Many therapeutic treatments of pathological conditions involve selective targeting of specific tissues or cells for destruction. For example, a goal in cancer therapy is to destroy only malignant cells while leaving normal cells undisturbed. As another example, a goal in ophthalmology is to destroy new blood vessels in the eye that can result in visual impairment if allowed to proliferate, while leaving normal existing blood vessels intact.
In the mammalian eye, macular degeneration is a pathological condition that results in proliferation of new blood vessels in the subretinal area. The new blood vessels proliferate from the choriocapillaris through defects in Bruch's membrane beneath or on top of retinal pigment epithelium (RPE), and form vascular membranes. While the presence of the new vessels themselves is not problematic, new vessels leak blood and other serous fluid which accumulate in surrounding spaces. It is this fluid accumulation that leads to visual impairment. For example, the accumulation of fluid can result in serous and hemorrhagic detachment of the RPE and neurosensory retina, and can lead to loss of vision due to fibrous deform scarring. Therefore, methods to prevent or control the growth of subretinal new blood vessels and/or to alter their "leakiness" have been devised to protect retinal integrity.
In the retina, both the large vessels and the capillaries normally have intact vessel walls. In the choroid, the large vessels normally have intact vessel walls but the capillary walls or membranes contain fenestrations or openings. Any endogenous or exogenous fluid present in these capillaries, for example, blood, serous fluid, solubilized drug, etc. will leak outside the vessels and into the surrounding area. An example of an exogenously administered drug is a photosensitizing drug that is administered to an individual for subsequent phototreatment with photodynamic therapy (PDT). PDT is a method for local and selective tissue or cellular destruction by the action of a particular wavelength of light on the photosensitizing drug. The wavelength of light is selected to correspond to the absorbance spectrum of the photosensitizing agent.
In normal vessels with intact membranes, an intravenously administered compound such as a photosensitizing agent is confined to the vessel lumen. The surrounding tissue, since it contains little if any photosensitizing agent, is not damaged by subsequent laser treatment. In addition, cytotoxic oxygen species such as hydroxyl or oxygen free radicals produced at the irradiation site have short diffusion distances and are similarly locally confined. Also, the low energy levels of the laser treatment in PDT spare normal adjacent tissues. Since there is no thermal damage, and since nonthermal light activation leads to only localized, selective photochemical thrombosis, PDT is selective for a specific area.
PDT ideally occurs when tissue levels of the photosensitizing agent are at a maximum. Neovascular tissue, like the normal choriocapillaries, have fenestrations in the vessel wall which allow some portion of the administered photosensitizing drug to escape from the lumen and into the surrounding tissue spaces. The leakage and pooling of fluid permits photosensitizing agent administered into a vessel to be located in both the vessel lumen and outside the vessel, leading to generalized tissue destruction in the area containing the photosensitizing agent.
One method to control fluid leakage from choroidal and new subretinal vessels is laser photocoagulation using lateral transfer of heat. Laser photocoagulation uses a cautery-like method to coagulate fluid escaping from the vessel wall. However, while it is effective to control fluid leakage in some patients, it is not entirely satisfactory. For example, it seldom confines the extent of damage to choroidal neovascular tissue, since there is heat-generated destruction of unaffected areas of the retina, including the neurosensory retina and RPE overlying the vascular leakage sites. Laser photocoagulation thus lacks the desired specificity to target only new blood vessels. Additionally, there is a persistent or recurrent choroidal neovascularization following repeated laser photocoagulation that frequently leads to more severe visual loss over time.
Another method to control fluid leakage from choroidal and subretinal vessels is PDT. PDT is more protective of normal tissue than laser photocoagulation because there is no heat applied so laser treatment may be localized to a specific area. PDT has gained wide clinical acceptance as a mechanism for producing localized, selective photochemical thrombosis. For example, PDT has been suggested as being able to play an important adjuvant role in treatment of cancers of the gastrointestinal tract and has been used to treat cancers of the esophagus, duodenum and colon. A photosensitizer prodrug, preferably aminolevulinic acid (ALA), is orally administered and is absorbed by the gastrointestinal tract. ALA is metabolized in vivo to protoporphyrin, the active photosensitizing agent. Protoporphyrin preferentially accumulates in the cytoplasm of neoplastic, versus normal, cells. A drawback of this treatment is that the oral route of administration of the agent leads to a weaker photosensitizing response than other routes of administration, e.g. intravenous administration.
Unfortunately, the results of PDT in ophthalmologic treatment have not been as promising; PDT is too nonspecific in that normal retinal vessels are damaged along with subretinal vessels. Also, there are unresolved issues with PDT such as the time interval between drug administration and light application, and the selective targeting of abnormal vessels with drug, light, or both.
Current methods in treating macular degeneration, such as laser photocoagulation, do not confine treatment to only new abnormal vessels. Thus, normal healthy blood vessels are destroyed, causing a decreased intraocular blood flow. In addition, laser treatment must continually be repeated as new vascularizations occur. Current methods in treating cancer are beginning to recognize the need to control the vascular supply to neoplastic cells.
Simply put, control of blood vessels is a way to treat certain pathological conditions such as macular degeneration and cancer. Macular degeneration results in new, inherently "leaky", blood vessels in the eye. These new leaky vessels allow fluid to escape and pool in the surrounding tissues. The accumulation of fluid results in scar formation which can damage the eye and lead to altered vision. In cancer, it is recognized that new blood vessels play a role in nourishing malignant cells. A goal in the treatment of both diseases is to destroy the new abnormal blood vessels but leave normal blood vessels undisturbed.
Thus, there remains a need for a therapeutic method to effectively target undesired and/or abnormal vessels while leaving normal vessels intact.